Insulin is a peptide secreted from pancreatic beta cells, which plays an important role in the regulation of blood sugar in the body. Diabetes mellitus is a kind of a metabolic disease in which insulin secretion is insufficient or normal functions are not made, which leads to increased blood glucose levels. Type 2 diabetes is the case in which insulin is not secreted properly or the secreted insulin is not properly processed in the body and the blood glucose levels are not controlled and so are raised. Type 2 diabetes is conventionally treated using a hypoglycemic agent containing a chemical material as an active ingredient or, for some patients, treated by administration of insulin. On the other hand, in Type 1 diabetes, the administration of insulin is essentially required.
Insulin therapy, which is currently widely used, is a method of administering insulin via injection before and after meals. Insulin is now available as an injection and is principally administered by subcutaneous injection, and the method of administration is different according to the action time. Insulin administration appears a more quick hypoglycemic effect than the drugs taken, and can be safely used even in environments in which the drugs are not available. Further, there is no limitation on the amount of the dose, but the administration of insulin must occur three times a day. Therefore, there are disadvantages such as patient fear of needles, the difficulty of administration, hypoglycemia symptoms, and weight gain due to long-term administration of insulin. The weight gain increases the risk of cardiovascular disease, which can lead to the side effect of lowered blood sugar control function.
A dual agonist capable of binding to both GLP-1 and two peptide glucagon receptors is currently being studied as a mechanism to concurrently treat both diabetes and obesity. The GLP-1 and the glucagon dual agonist inhibit food intake of GLP-1, promote satiety, show lipolytic function of glucagon, maintain blood sugar reduction and show a high effect on reducing body weight, thereby having high possibility of use as new therapeutic agents.
The present inventors have found that insulin and the dual agonist are inconvenient in that administration must be made daily to the patient due to a short half-life, and have suggested, as a technique of maintaining the activity of protein drug and achieving improved stability at the same time in order to solve the abovementioned problems, a long-acting protein conjugate in which a conventional physiologically active polypeptide and an immunoglobulin Fc region are covalently combined with each other by a non-peptidyl polymer linker (Korean Patent No. 10-0725315). In particular, the inventors have confirmed that the sustainability of the in vivo effects of both the long-acting insulin conjugate and long-acting dual agonist conjugate is dramatically increased (Korean Patent No. 10-1058290, Korean Patent Application No. 10-2014-0022909 and Korean Patent Application Publication No. 10-2012-0139579).
However, there are problems in that side-effects such as weight gain occur upon administration of GLP-1/glucagon dual agonist. Therefore, there still remains a need for the development of a therapeutic agent for diabetes having reduced side-effects, frequency and dosage